A. Benedet

Plasma Biomarkers for Neocortical Tau Burden.

Importance Phosphorylated tau-217 (p-tau217) is now an established plasma biomarker for assessing amyloid-β pathology in individuals at risk of Alzheimer disease. However, its performance in identifying advanced neocortical neurofibrillary tangle burden remains suboptimal. Precise assessment of tau pathology is increasingly critical for the rational implementation of anti-amyloid therapies and developing anti-tau interventions. Improved biofluid biomarker-based tau staging could enhance patient stratification and optimize participant selection for clinical care and therapeutic trials. Objective To develop and validate a multiprotein plasma panel to improve identification of neocortical tau pathology beyond p-tau217 alone. Design, Setting, and Participants This multicenter cohort study included 2 independent observational cohorts, Swedish BioFINDER study and Translational Biomarkers in Aging and Dementia (TRIAD). Cross-sectional clinical data and blood samples were collected between 2017 and 2024. Participants included 560 individuals spanning the clinical spectrum from cognitively unimpaired to dementia. These data were analyzed from January 2025 to May 2026. Exposures Plasma concentrations of 125 proteins measured using Nucleic Linked Immuno-Sandwich Assay central nervous system panel. Main Outcome and Measure Advanced tau pathology defined as tau positron emission tomography (PET) uptake within Braak stage V and VI regions. Predictive performance of biomarker models was evaluated using area under the receiver operating characteristic curve (AUC). Results The study included 560 amyloid-positive participants (BioFINDER: n = 431; mean [SD] age, 73.6 [7.0] years; 212 female [49.2%] and 219 male [51.8%]; TRIAD: n = 129; mean [SD] age, 70.4 [8.3] years; 76 female [58.9%] and 53 male [41.1%]). Using multivariable logistic regression approaches, a 7-protein panel was found in BioFINDER to identify tau PET uptake within Braak stage V and VI regions. When compared with p-tau217 (AUC, 0.86-0.88; 95% CI, 0.82-0.94), this multiprotein panel was associated with improved identification in both discovery and validation cohorts (AUC, 0.92-0.94; 95% CI, 0.89-0.98; DeLong P < .001). This reduced the proportion of individuals classified within the intermediate-risk range (between paired sensitivity and specificity thresholds) in the validation cohort by 14.7% to 21.0%. Conclusions and Relevance This multicohort study demonstrated how including additional plasma proteins significantly enhanced the performance of p-tau217 in predicting advanced tau pathology among amyloid-positive individuals. This suggests a multiprotein approach may offer a viable and scalable alternative to tau PET staging in clinical or research settings.

Predicting continuous amyloid PET levels with CSF and plasma brain‐derived p‐tau217

Staging amyloid beta (Aβ) burden along a continuous spectrum provides clinically relevant information. Conventional phosphorylated tau (p‐tau)217 reliably identifies amyloid positron emission tomography (PET) positivity, but its ability to capture the full Aβ continuum is limited. Recently developed brain‐derived (BD) p‐tau217 assays enrich for central nervous system tau species and may improve specificity.

Lifestyle and psychosocial protective factors drive healthy aging and modulate inflammatory and metabolic pathways.

Lifestyle habits, cognitive reserve, and affective reserve (secure attachment, extraversion, psychological resilience) predict resilience in the oldest-old, though the underlying biological mechanisms remain unclear. This study explored relationships between these protective factors, 120 + NULISA CNS blood biomarkers, and multidimensional health outcomes (global cognition, mental health, walking speed) in 401 dementia-free participants (age 83-87) from the InveCe.Ab study. Using sparse partial least squares (sPLS) regression, eight biomarkers were stably associated with the protective factors: HBA1, DDC, IFNG, IL15, GOT1, ACHE, SNAP25, and SNCB. Structural equation modeling (SEM) showed that the three protective factors exerted an independent and domain-specific effect on health outcomes. Moreover, lifestyle habits were associated with ACHE (β = 0.26), IL15 (β = 0.22), and GOT1 (β = 0.28); affective reserve showed inverse associations with IFNG (β = -0.13) and IL15 (β = -0.31), and GOT1 (β = -0.18). Regarding health domains, SNAP25 was inversely related to global cognition (β = -0.10), while SNCB was associated with global cognition (β = 0.16) and walking speed (β = 0.13). Notably, no significant mediated effects were found, suggesting that the clinical benefits observed were not directly driven by the aforementioned biological pathways. The present study paves the way for further investigations on the biological mechanisms underlying resilient aging, while further demonstrating the key protective role of individual habits and psychosocial characteristics during the life course.

Blood-based biomarkers of Alzheimer’s disease and neurodegeneration in an indigenous African cohort using both Simoa and NULISA platforms

In low- and middle-income countries, Alzheimer’s disease (AD) constitutes a growing public health burden. However, AD biomarkers research remains underrepresented in African populations. This study assesses core biomarkers of AD and their relevance in the African context as potential aid in clinical diagnosis. Nigerian older adults from VALIANT cohort (n = 967) underwent biomarker quantification in plasma (p-tau217, GFAP, NfL, Aβ42 and Aβ40) employing both the Single Molecule Assay (Simoa, Quanterix) and Nucleic acid-Linked Immuno-Sandwich Assay (NULISA, Alamar). Biomarkers were associated with disease severity in clinical-diagnostic and clinical-biological groups, with stepwise increases of p-tau217, NfL and GFAP from cognitively unimpaired to dementia (p < 0.05). Results were consistent across platforms. Comparison between sexes showed higher biomarker levels in male participants across diagnostic groups. A significant effect of apoE-E4 proteotype on p-tau217 levels, after adjusting for age and sex was identified. These findings support the application of plasma AD biomarkers in the African context and the relevance of further AD biomarker research in diverse populations.

Analytical validation and amyloid-status discrimination of a high-throughput, research-use-only plasma p-Tau217 immunoassay